Submissions for variant NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro)

dbSNP: rs1555805237

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV002506400	SCV002817153	uncertain significance	Hypercholesterolemia, familial, 1	2022-10-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1300A>C (p.Thr434Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PM5 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) (ClinVar ID 251774) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1301C>T (p.Thr434Met)(ClinVar ID 251775) - Unknown significance by these guidelines - NM_000527.5(LDLR):c.1301C>A (p.Thr434Lys) (ClinVar ID 251773) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586847	SCV000697195	uncertain significance	not provided	2016-07-11	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1300A>C (p.Thr434Pro) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (MutationTaster not captured due to low p-value). This variant was found in 1/120910 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221284	SCV001393317	pathogenic	Familial hypercholesterolemia	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 434 of the LDLR protein (p.Thr434Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypercholesterolemia (internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 496018). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. This variant disrupts the p.Thr434 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10634824, 11668627), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002384285	SCV002689839	likely pathogenic	Cardiovascular phenotype	2024-03-28	criteria provided, single submitter	clinical testing	The p.T434P variant (also known as c.1300A>C), located in coding exon 9 of the LDLR gene, results from an A to C substitution at nucleotide position 1300. The threonine at codon 434 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH) (Ambry internal data). Two other variants at the same codon, p.T434K (c.1301C>A) and p.T434R (c.1301C>G), have also been described in association with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30; Real J et al. BMJ Case Rep, 2018 Jan;2018:pii: bcr-2017-222155). In addition, based on internal structural assessment, this alteration destabilizes the LDL receptor B domain (Jeon H et al. Nat. Struct. Biol., 2001 Jun;8:499-5040). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV002506400	SCV004827118	uncertain significance	Hypercholesterolemia, familial, 1	2023-06-28	criteria provided, single submitter	clinical testing